Many organophosphate (OP) compounds are potent cholinesterase inhibitors and have extensively been used as pesticides and insecticides in agriculture, as a flame retardant in plastics and rubbers, and even as a gasoline additive [1-3]. Each year, there are approximately three million pesticide poisonings world-wide resulting in more than 200,000 deaths [1]. Long term exposures to these OP compounds in commercial products have been linked to several adverse health effects and permanent damages to our ecosystem. The search for enzymes that act as bioscavengers against toxic OP compounds has become an intense research topic. In this context, human serum paraoxonase, PON1 could become a promising scavenger against highly toxic OP compounds because 1) it is in human serum, 2) it can hydrolyze OP compounds, and 3) it displays large pH optima and performs optimally at physiological temperature [5-7]. However, PON1's physiological role has not yet been unambiguously identified. It is considered to be a promiscuous enzyme [6]. In addition, PON1 is polymorphic in human populations and different individuals also express widely different levels of this enzyme [5]. The proposed research is to re-engineer PON1 using a new approach that integrates both conformational dynamics and evolution information by 1) characterizing its catalytic activities, 2) identifying conformational diversities of the enzyme, 3) exploring the effects of polymorphisms on substrate specificity and stability, and 4) integrating these enzymatic properties into the Rosetta Enzyme Design method [10, 11]. The proposed research will therefore, not only focus on characterizing reaction mechanisms of PON1 at its active site, but also include dynamical information beyond this site, such that the redesigned enzyme will be more catalytic efficient and highly expressible. The resulting computational design will concurrently be tested and characterized in the wet-lab. The experimental biochemistry will be included as restraint information to optimize the designed cycle further. The research proposal is the interplay between theory, experiments, and computations which will facilitate a rapid progress for the proposed research. The candidate's main career goals are to become a tenured, endowed professor at a Tier 1 research institution and to have a multidisciplinary research group that works on methodology developments and applications to environmental health sciences and biotechnology. She believe that in less than a decade, computational structural biology and cellular bioinformatics will have come together to advance research in protein engineering; at this point, in her research plans for the K01 fellowship, she aim to get the right breadth of expertise to be positioned precisely at that intersection. In this context, she is eager to take her computational expertise developed in the McCammon and Dobson laboratories and apply it to the enzyme design that Professor Baker, one of the world renowned expert in the field, is pursuing. Public Health Relevance: The new Rosetta Enzyme Design is introduced and applied to re-engineer the human paraoxonase to be used as effective bioscavengers that sequester highly toxic organophosphate compounds commonly found in commercial products. This proposal thus has direct relevance impact in environmental protections and biotechnologies.